During T cell development, autoreactive T cells are eliminated in the thymus through a mechanism known as clonal deletion. As a result, mature cells exported to the peripheral lymphoid organs do not react to self- antigens and autoimmune diseases rarely develop. T cells which can recognize self-antigens not expressed intrathymically are not deleted and represent a potential danger. Autoimmunity may be secondary to a failure of intra-thymic deletion of autoreactive T cells, to a failure to induce peripheral tolerance, or to a breaking of established immunological tolerance. Our studies have focused on understanding the pathogenesis of the autoimmune state, the role of cytokines in mediating autoimmune tissue damage, and the treatment of established autoimmune diseases by modulation of the cytokine phenotype of the disease inducing T cells: 1) The mechanisms responsible for inducing tolerance to certain antigens are not completely functional during the first week of age since thymectomy of three day old mice (3dTx) is followed by the development of organ- specific autoimmune disease. The majority of cells in the lymphoid tissues of 3dTx mice appear to have undergone polyclonal T cell activation and demonstrated enhanced responses in the syngeneic mixed leukocyte reaction (SMLR). A direct role for the SMLR reactive T cells in the pathogenesis of disease post-3dTx was demonstrated in studies in which intrathymic tolerization to complexes of self-peptides and MHC class II antigens expressed on adult antigen-presenting cells prevented organ-specific disease. 2) Inflammatory immune responses or Delayed Type Hypersensitivity (DTH) reactions are mediated by CD4+ Th1 T cells which produce interferon-gamma (IFN-gamma), but little IL-4, while CD4+ Th2 populations which produce large amounts of IL-4 and IL-5 mediate immune responses characterized by high levels of non-complement binding IgG, IgE, and eosinophil mediated cytotoxicity, but no organ specific tissue destruction or inflammation. Our recent understanding of the regulation of cytokine production in vitro and in vivo has allowed us to develop protocols for the antigen-specific induction of Th2 populations which may then be used in the therapy of diseases mediated by harmful DTH reactions such as experimental allergic encephalomyelitis (EAE), autoimmune diabetes, uveitis, graft rejection, and contact sensitivity.